Might the virus be slowly gaining the ability to jump from human-to-human, the one trait it lacks for initiating a pandemic?

IN APRIL and May of 1997, an unusually virulent form of bird flu wiped out all the birds in one poultry farm in Hong Kong and killed three-quarters of the birds in two other farms. As avian influenza viruses were not known to infect humans, the outbreak was not regarded as a direct threat to human health. But alarm bells rang when it was discovered in August that a three-year-old boy who died of pneumonia three months earlier had been infected with the very same strain of bird flu. By the end of December that year, 17 more Chinese in Hong Kong were stricken by the same bird flu virus and six of them died of it. The city officials contained the epidemic by slaughtering all one and a half million chicken in Hong Kong and halting poultry imports from mainland China. That, however, did not stop the same strain of bird flu from surfacing again in Hong Kong in February 2003 when it infected just two persons and killed one of them.

But the frightening swiftness with which the Severe Acquired Respiratory Syndrome (SARS), which appeared for the first time a month later, spread to 20 countries on all the continents, infecting 8,000 people and killing more than 800, showed all too clearly how much havoc an influenza pandemic could unleash in a world that is closely knit by air travel and economic ties. The three influenza pandemics of the last century too are a grim warning. The pandemic of 1918 is thought to have killed 40 million worldwide. The pandemics of 1957 and 1968 together claimed over three million lives.

Influenza viruses are classified into three types, A, B, and C. The latter two infect only humans but have never set off pandemics. It is the type A influenza viruses, which also infect a wide variety of animals including aquatic birds that serve as their natural reservoirs, that are dangerous. Type A viruses are further classified according to two proteins on their outer coat, hemagglutinin (H) that give the viruses entry into cells and neuraminidase (N) that is essential for viral replication. Moreover, the two proteins are the principle targets of the host's immune system. Duplication of the virus' genetic material in an infected cell is, however, imperfect and introduces changes in the viral genes (termed mutation) that then alter the structure of its proteins. Small changes in the surface proteins of influenza strains already infecting humans helps them escape the clutches of the host immune system, causing yearly outbreaks of flu.

When different influenza strains infect the same cell, they can exchange genes and produce hybrid forms. Such reassortment of avian strains and human influenza viruses can create novel hybrids to which people have no immunity. The two influenza strains that caused the 1957 and 1968 pandemics, for instance, had components of both human and avian viruses. The pig, which can be infected by both human and bird influenza viruses, is believed to serve as a "mixing vessel" that produces reassorted virus strains.

The origin of the strain responsible for the dreadful pandemic of 1918 is puzzling, says Jeffrey Taubenberger of the Armed Forces Institute of Pathology in the United States, who was involved in resurrecting the strain for laboratory study from human autopsy specimens. Although the genes of the 1918 strain did have some avian features, analysis has shown that this strain was more closely related to human and swine influenza families. Yet, the strain's gene sequences are consistent neither with direct reassortment from a known avian strain nor with adaptation of an avian strain in pigs. Although the 1918 virus may well have been an avian strain, it could have emerged into circulation among humans from an as yet unknown animal host as the SARS virus did, writes Dr. Taubenberger in a recent issue of Scientific American.

The strain of avian influenza that first surfaced among humans in 1997, which has been classified as influenza type A(H5N1), has steadily grown more dangerous and more likely to produce the next pandemic influenza. It caused widespread outbreaks of bird flu among poultry that were unprecedented in scale and lethality. The outbreaks began in 2003 and rapidly engulfed eight Asian countries, leading to the death or slaughter of more than 120 million birds. In Thailand and Vietnam, 35 persons who had direct contact with infected poultry became ill between January and March 2004 and 24 of them died.

After a brief lull, the bird flu returned in July last year, with fresh outbreaks being reported from China, Cambodia, Indonesia, Thailand, Vietnam, and subsequently Malaysia. From August through October, 10 persons had contracted the disease in Thailand and Vietnam, and eight died of it. Although more than a million birds were culled, H5N1 has proved resilient. "The new wave of avian influenza outbreaks in Vietnam and Thailand clearly shows that the avian virus remains endemic in Asia," observed the Food and Agriculture Organization (FAO) and the World Animal Health Organisation (OIE) in a joint press statement recently. "Recent experience shows that it may be impossible to eradicate the virus soon," the statement added.

Since mid-December, 13 persons in Vietnam are known to have been infected by the H5N1 virus, all but one of whom perished. It was recently established that a young woman from neighbouring Cambodia, who came to Vietnam for treatment and died there, was infected with an influenza A(H5) virus.

As before, most human incidents of H5N1 influenza could be traced back to close contact with infected birds. However, a paper published recently in the New England Journal of Medicine provides strong evidence that a young Thai woman fell victim to H5N1 influenza last September after nursing her critically-ill 11-year-old daughter; both of them succumbed to the flu. The woman's sister, who too had nursed the girl, was also infected but survived.

Might the virus be slowly gaining the ability to jump from human-to-human, the one trait it lacks for initiating a pandemic? Thai and U.S. researchers point out in their NEJM paper that although the girl might have passed on the infection to her mother and aunt, it was reassuring that no further transmission of the virus was detected. It has been widely feared that either by mutation or through reassortment with circulating human influenza viruses, the H5N1 might develop the ability for efficient human transmission. Neither had happened, say the researchers.

But nevertheless concern remains high as more family clusters have appeared in the latest outbreak. A 42-year-old Vietnamese salesman was recently discharged from Hanoi's Hospital for Tropical Diseases where his older brother had died. But in this case there is also the possibility that both brothers might have might have picked up the H5N1 virus by eating a traditional Vietnamese dish containing congealed raw duck blood. The WHO and Cambodian authorities are investigating reports that the brother of the Cambodian woman who died in Vietnam had also died of similar symptoms and other members of the family have fallen sick.

Why has the H5N1 not reassorted with a human influenza virus despite ample opportunity to do so? It is tempting to conclude that if H5N1 could reassort, it should have done so by now, remarked Klaus Stohr, head of the World Health Organisation's Global Influenza Programme, in an editorial in NEJM. The explanation may lie in sheer statistical luck. It could also be that reassortment has occurred but has resulted in viruses that are not viable, not pathogenic, or not more easily transmitted among humans than H5N1 currently is. If so, this would be good news and H5N1 could be moved a notch down on the watch list of viruses with the potential to cause a pandemic, he observed. To answer this question, experiments to mimic reassortment in the laboratory were being carried out but may not be completed before the end of this year, he added.

A report prepared last month (January 2005) by the WHO Secretariat noted the similarities between the present H5N1 virus and the strain that caused the 1918 pandemic, which included the gradual adaptation of an avian virus to a more human-like one, the severity of disease and its concentration in young and healthy people. But the report also pointed out that an avian influenza virus would probably lose some of its pathogenicity when it acquires the improved transmissibility needed to ignite a pandemic.

If a pandemic strain does appear, given the high level of global traffic, the virus may spread rapidly, giving little or no time to prepare, according to the WHO. Modelling studies suggest that the pandemic could claim between two million to over seven million lives worldwide. Vaccines, antiviral agents and antibiotics to secondary infections will be in short supply and will be unequally distributed. Medical facilities can be overwhelmed and there could be significant shortage of personnel to provide essential services, warns the WHO.

Conditions favouring the emergence of a pandemic are increasingly being met. "It is therefore prudent for all countries, supported by WHO, to undertake or intensify preparedness activities as a matter of urgency," said the WHO Secretariat's report.